Human intestinal epithelial cell survival: differentiation state-specific control mechanisms

To investigate whether human intestinal epithelial cell survival involves d istinct control mechanisms depending on the state of differentiation, we an alyzed the in vitro effects of insulin, pharmacological inhibitors of Fak, MEK/Erk, and PI3-K/Akt, and integrin (beta1, beta4)-blocking antibodies on the survival of the well-established human Caco-2 enterocyte-like and HIEC- 6 cryptlike cell models. In addition, relative expression levels of six Bcl -2 homologs (Bcl-2, Bcl-X-L, Mcl-1, Bax, Bak, and Bad) and activation level s of Fak, Erk-2, and Akt were analyzed. Herein, we report that 1) the enter ocytic differentiation process results in the establishment of distinct pro files of Bcl-2 homolog expression levels, as well as p125(Fak), p42(Erk-2), and p57(Akt) activated levels; 2) the inhibition of Fak, of the MEK/Erk pa thway, or of PI3-K, have distinct impacts on enterocytic cell survival in u ndifferentiated (subconfluent Caco-2, confluent HIEC-6) and differentiated (30 days postconfluent Caco-2) cells; 3) exposure to insulin and the inhibi tion of Fak, MEK, and PI3-K resulted in differentiation state-distinct modu lations in the expression of each Bcl-2 homolog analyzed; and 4) Fak, beta1 and beta4 integrins, as well as the MEK/Erk and PI3-K/Akt pathways, are di stinctively involved in cell survival depending on the state of cell differ entiation. Taken together, these data indicate that human intestinal epithe lial cell survival is regulated according to differentiation state-specific control mechanisms.